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Suppression of Thymidine Phosphorylase-mediated Angiogenesis and Tumor Growth by 2-Deoxy-L-ribose¹

Departments of Cancer Chemotherapy, Institute for Cancer Research [H. U., T. F., Y. N., R. I., T. G., M. H., T. S., S-i. A.] and Dermatology [H. U., S. M., T. K.], Kagoshima University, Faculty of Medicine, Kagoshima 890-8520, and Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka [M. Ok., M. On., M. K.], Japan

Thymidine phosphorylase (TP), an enzyme involved in the reversible conversion of thymidine to thymine, is identical to an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF). Both TP and one of the TP-degradation products of thymidine 2-deoxy-D-ribose (dRib) display endothelial cell chemotactic activity in vitro and angiogenic activity in vivo. Recently, we demonstrated that 2-deoxy-L-ribose (lRib) could abolish the inhibitory effect of dRib on hypoxia-induced apoptosis. This suggested that lRib may be a useful inhibitor of dRib and thereby of TP functions. Therefore, we investigated the ability of lRib to inhibit the range of biological activities of TP and dRib. lRib suppressed both dRib-induced endothelial cell migration in a chemotaxis assay and endothelial tube formation induced by dRib in a collagen gel. lRib could also suppress the biological effects of TP in vivo assays of angiogenesis and tumor growth. Thus, in a corneal assay of angiogenesis, lRib inhibited angiogenesis induced by the implantation of recombinant TP. In a dorsal air sac assay of angiogenesis, lRib inhibited angiogenesis induced by the implantation of KB cells overexpressing TP (KB/TP). In a tumor growth assay, lRib treatment considerably decreased the growth rate of KB/TP cells xenografted into nude mice and also resulted in an increase in the proportion of apoptotic cells in KB/TP tumors.

These findings demonstrate that TP and dRib play an important role in angiogenesis and tumor growth, and that these effects can be inhibited by lRib. Thus, lRib is a potentially useful agent for the suppression of TP-dependent angiogenesis and tumor growth.

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